Rapid access to novel 1,2,3-triazolo-heterocyclic scaffolds via tandem knoevenagel condensation/azide-alkyne 1,3-dipolar cycloaddition reaction in one pot

Article abstract of DOI:10.1021/co500070e

An operationally simple, one-pot, two-step cascade method has been developed to afford biologically important fused 1,2,3-triazolo-heterocyclic scaffolds from 2-alkynyl aryl(heteroaryl) aldehydes and phenacyl azides. This unique atom economical transformation engages four reactive centers (aldehyde, alkyne, active methylene, and azide) under metal-free catalysis.

Full text of DOI:10.1021/co500070e

Subscriber access provided by UNIV OF WATERLOO
Article
Rapid Access to Novel 1,2,3-Triazolo-Heterocyclic
Scaffolds via Tandem Knoevenagel Condensation/Azide-
Alkyne 1,3-Dipolar Cycloaddition Reaction in One Pot
Ram Awatar Maurya, Praveen Reddy Adiyala, D Chandrasekhar,
Chada Narsimha Reddy, Jeevak Sopanrao Kapure, and Ahmed Kamal
ACS Comb. Sci., Just Accepted Manuscript • Publication Date (Web): 19 Jun 2014
Downloaded from http://pubs.acs.org on June 21, 2014
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
ACS Combinatorial Science is published by the American Chemical Society. 1155
Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the
course of their duties.

Page 1 of 39
ACS Combinatorial Science
1
2
3
4
5
6
7
8
9
Rapid Access to Novel 1,2,3-Triazolo-
Heterocyclic Scaffolds via Tandem Knoevenagel
Condensation/Azide-Alkyne 1,3-Dipolar
Cycloaddition Reaction in One Pot
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Ram Awatar Maurya,* Praveen Reddy Adiyala, D. Chandrasekhar, Chada Narsimha Reddy,
Jeevak Sopanrao Kapure, and Ahmed Kamal*
O
O
R2
R2
O
Piperidinium
acetate
N
N
N
AcOH
Reflux
+
R1
R1
N
EtOH, rt
O
R1
AcO
N
3
R2
33 examples; 78-93% yield; high atom economy
ACS Paragon Plus Environment

ACS Combinatorial Science
Page 2 of 39
1
2
3
4
5
6
7
8
9
Rapid Access to Novel 1,2,3-Triazolo-Heterocyclic
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scaffolds
via
Tandem
Knoevenagel
1,3-Dipolar
Condensation/Azide-Alkyne
Cycloaddition Reaction in One Pot
Ram Awatar Maurya,* Praveen Reddy Adiyala, D. Chandrasekhar, Chada Narsimha Reddy,
Jeevak Sopanrao Kapure, and Ahmed Kamal*
Division of Medicinal Chemistry and Pharmacology, CSIR-Indian Institute of Chemical
Technology, Hyderabad-500007, India
KEYWORDS: Knoevenagel condensation, azide-alkyne cycloaddition, tandem reaction,
triazole, pyrazolo-pyridine, β-carboline, isoquinoline
ABSTRACT:
H
O
O
R2
R2
O
Piperidinium
acetate
(one eq.)
N
AcOH
Reflux
N
N
R1
OAc
+
N
Ethanol,
rt
O
R1
R1
N3
R2
33 examples; 78-93% yield; high atom economy
ACS Paragon Plus Environment
1

Page 3 of 39
ACS Combinatorial Science
1
2
3
4
5
6
7
8
9
An operationally simple, one pot, two-step cascade method has been developed to afford
biologically important fused 1,2,3-triazolo-heterocyclic scaffolds from 2-alkynyl aryl(heteroaryl)
aldehydes and phenacyl azides. This unique atom economical transformation engages four
reactive centres (aldehyde, alkyne, active methylene, and azide) under metal-free catalysis.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
INTRODUCTION
The azide-alkyne 1,3-dipolar cycloaddition reaction has attracted an enormous amount of interest
over the past decade. Today it is widely used in classical organic/combinatorial synthesis,1
medicinal chemistry/drug discovery programs,2 and has also made a major impact in
polymer/material science,3 and in the field of chemical biology.4 The ease and efficiency of this
reaction has been recognized in organic/aqueous solvents over a range of temperature varying
from ambient to heating.5 Moreover, both terminal and internal alkynes have been efficiently
used as compatible substrate with a high order of regioselectivity. In addition to the
intermolecular format, many research groups have demonstrated intramolecular version of azide-
alkyne 1,3-dipolar cycloaddition reaction.6 However, most of the reported intramolecular
strategies of the azide-alkyne 1,3-dipolar cycloaddition have largely utilized terminal alkyne in a
multi-step format to facilitate the reaction with limited applications to internal alkynes.7
Intramolecular azide-alkyne cycloaddition provides an elegant access to interesting two
annulated cyclic ring system. Thus, developing one pot, novel tandem process for intramolecular
azide/internal alkyne 1,3-dipolar cycloaddition would open a rapid access to diverse heterocyclic
scaffold.8
Efficient transformation of simple substrates into structurally novel and multifarious heterocycles
constitutes a great challenge in organic chemistry. Tandem reactions which allow formation of
multiple bonds in one pot operation have been recognised as a powerful tool to address these
ACS Paragon Plus Environment
2

ACS Combinatorial Science
Page 4 of 39
1
2
concerns.9 Presented in this letter is a tandem process which involves an intermolecular
Knoevenagel condensation-intramolecular azide/internal alkyne 1,3-dipolar cycloaddition
reaction in one pot that eventually leads to very interesting fused 1,2,3-triazolo-heterocycles. The
strategy has been generalized on three distinct substrates bearing indole, pyrazole, and benzene
core motifs. We have also demonstrated efficient conversion of fused 1,2,3-triazolo-heterocycles
into β-carboline, pyrazolo-pyridine, and isoquinolines. These heterocycles are very important
scaffolds as they are found in numerous synthetic and natural products of biological and
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
pharmacological interest (Figure 1).10
HO
O
R1
RO
N
N
N
N
N
N
Ph
OH
N
H
R
Cl
Pyrazolo-pyridines
(Selective Inhibitors of A1 Adenosine Receptors)
OH
Pyridindolol
(beta-galactosidase inhibitor)
3-(2-Pyridinyl)isoquinoline
(Adenosine A3 Receptor Ligands)
Figure 1. Chemical structure of some biologically important β-carboline, pyrazolo-pyridine, and isoquinoline.
RESULTS AND DISCUSSION
Indole is considered as a privileged scaffold and is found in a plethora of synthetic and natural
products of medicinal interest.11 Starting from 2-(arylethynyl)-indole-3-carbaldehyde 1 and
phenacyl azide 2, the proposed tandem Knoevenagel condensation-azide/internal alkyne 1,3-
dipolar cycloaddition reaction should lead to the formation of fused 1,2,3-triazolo-β-carbolines
3. Thus, firstly we sought to optimize the reaction by taking 1-benzyl-2-(phenylethynyl)-1H-
indole-3-carbaldehyde 1{1} and 2-azido-1-phenylethanone 2{1} as reaction partners (Table 1).
ACS Paragon Plus Environment
3

Page 5 of 39
ACS Combinatorial Science
1
2
3
4
5
6
Table 1. Optimization of one pot, tandem Knoevenagel condensation-azide/internal alkyne 1,3-dipolar
cycloaddition reaction.a
7
8
O
O
O
9
Ph
H
Catalyst
Solvent
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
+
N
Ph
N
N
N
N3
2{1}
N
Ph
Ph
Ph
Ph
3{1,1}
1{1}
Entry
Catalyst/additive
Catalyst/additi
Solvent
Temperature
Yield of
ve mol%
20
3{1,1} (%)b
1
2
Piperidine
Piperidine
DBU
NaOH
p-TsOH
AcOH
Sc(OTf)3
PA
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
rt
12
NI
8
20
reflux
3
20
rt
rt
4
20
NI
NI
NI
NI
35
55
88
88
87
81
87
5
20
rt
6
20
rt
7
20
rt
8
20
rt
9
PA
50
rt
10
11
12
13
14
PA
100
150
100
100
100
rt
PA
rt
PA
reflux
rt
PA
Acetonitrile
PA
Methanol
rt
a 1{1} (0.20 mmol), 2{1} (0.20 mmol), solvent (2.0 ml), catalyst, stir, 24 h. bIsolated unoptimized yields. NI = Not isolated. rt = room
temperature. PA = Piperidinium acetate
A number of base (piperidine, DBU, NaOH) and acid [p-TsOH, AcOH, Sc(OTf)3] catalysts were
attempted but none of them lead to a satisfactory yield of 3{1,1} either at ambient temperature or
under reflux condition (Table 1, entry 1-7). Under basic conditions, substrate 1{1} remained
largely unreacted whereas 2{1} was fully consumed. A careful survey of the literature revealed
that the anion obtained after deprotonation of active methylene 2{1} with a base undergoes
decomposition.12 We were pleased to achieve complete conversion of both 1{1} and 2{1} (TLC)
and high yield of 3{1,1} using piperidinium acetate as an additive (100 mol%) at ambient
ACS Paragon Plus Environment
4

ACS Combinatorial Science
Page 6 of 39
1
2
temperature (Table 1, entry 10).13 The structure of 3{1,1} was assigned with the help of ESI-MS,
1H NMR, 13C NMR, IR, and HRMS data [IR spectra of 3{1,1} did not show any band
corresponding to azide and alkyne; 13C NMR of 3{1,1} did not show any alkyne carbon in typical
acetylene region]. Refluxing the reaction mixture or further increasing the amount of the
additive (150 mol%) did not lead to any improvement. Methanol and acetonitrile were also found
suitable solvents for the reaction.
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O H
AcO
O
Ph
Piperidinium
acetate
N
N
H
2a
N3
COPh
N
-H2O
N
-AcOH
N
N
N
Bn
N
Bn
4{1}
Ph
1{1}
Ph
Bn
Ph
5{1}
- Piperidine (as piperidinium acetate)
O
N
- Piperidine
(as piperidinium
acetate)
Ph
COPh
N3
N
3{1,1}
N
N3
Ph
N
N
N
COPh
Bn
Bn
N
Bn
6{1}
6'{1}
Ph
Ph
7{1}
Scheme 1. A plausible mechanism for piperidinium acetate mediated tandem Knoevenagel condensation-
azide/internal alkyne 1,3-dipolar cycloaddition reaction.
Piperidinium acetate mediated reaction can be explained as depicted in Scheme 1. Substrate 1{1}
reacts with piperidinium acetate to yield an imininium acetate 4{1} which is attacked by enol
2{1} leading to the formation of 5{1}. The intermediate 5{1} might lead to the formation of
3{1,1} in two different pathways depending on whether piperidine is lost before or after
azide/alkyne 1,3-dipolar cycloaddition reaction. It is not easy for the Knoevenagel adduct 6’{1}
ACS Paragon Plus Environment
5

Page 7 of 39
ACS Combinatorial Science
1
2
3
4
5
6
7
8
9
to undergo intramolecular azide/alkyne cycloaddition due to azide/alkyne proximity limitations.
Since 6’{1} (and even 6{1}) was never isolated in our reaction conditions, it might be assumed
either 6{1} was preferentially formed or reaction proceeded via alternative pathway where
elimination of piperidine occurred after azide/alkyne cycloaddition. However, a possibility of
piperidine mediated isomerisation of 6’{1} to 6{1} cannot be ruled out.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3{1,1} R = Bn, R1 = Ph, R2 = Ph (88%)
3{1,2} R = Bn, R1 = Ph, R2 = 4-Cl-C6H4 (83%)
1
2
3{1,3}
R = Bn, R = Ph, R = 4-F-C6H4 (91%)
3{1,4} R = Bn, R1 = Ph, R2 = 4-MeO-C6H4 (86%)
3{1,5} R = Bn, R1 = Ph, R2 = 4-Ph-C6H4 (90%)
3{1,6} R = Bn, R1 = Ph, R2 = 4-Me-C6H4 (80%)
3{1,7} R = Bn, R1 = Ph, R2 = 3-MeO-C6H4 (82%)
O
R2
O
O
1
2
3{1,8}
R = Bn, R = Ph, R = 4-(pyrrolidin-1-yl)phenyl (80%)
N
H
N
N
Piperidinium acetate
Methanol
3{2,1} R = Bn, R1 = 4-MeC6H4, R2 = Ph (81%)
+
R2
3{2,2} R = Bn, R1 = 4-MeC6H4, R2 = 4-Cl-C6H4 (80%)
3{2,5} R = Bn, R1 = 4-MeC6H4, R2 = 4-Ph-C6H4 (83%)
3{2,6} R = Bn, R1 = 4-MeC6H4, R2 = 4-Me-C6H4 (81%)
N
N
N3
R1
R
R1
R
2
1
2
1
3
3{3,2}
R = Bn, R = n-pentyl, R = 4-Cl-C6H4 (80%)
3{3,6} R = Bn, R1 = n-pentyl, R2 = 4-Me-C6H4 (81%)
3{4,2} R = Me, R1 = n-pentyl, R2 = 4-Cl-C6H4 (78%)
3{4,6} R = Me, R1 = n-pentyl, R2 = 4-Me-C6H4 (80%)
O
O
O
O
H
H
H
H
N
N
N
N
Ph
Ph
Ph
Ph
1{2}
1{3}
1{1}
Diversity points in substrate 1
1{4}
O
O
O
O
O
O
N3
N3
N3
2{1}
N3
N3
N3
2{3}
Ph
O
Cl
F
2{5}
2{6}
2{2}
2{4}
O
O
O
N3
N3
N
2{7}
2{8}
Diversity points in substrate 2
Figure 2. Synthesis of a library of fused 1,2,3-triazolo-β-carbolines 3 through tandem Knoevenagel condensation-
azide/internal alkyne 1,3-dipolar cycloaddition reaction. Bn = PhCH2, values in parenthesis represent isolated
unoptimized yields.
ACS Paragon Plus Environment
6

ACS Combinatorial Science
Page 8 of 39
1
2
3
4
5
6
7
8
9
Having optimized the tandem strategy with the substrates 1{1} and 2{1}, a series of fused 1,2,3-
triazolo-β-carbolines 3 (Figure 2) were synthesized in high yields following the same protocol. It
should be noted that azide-alkyne click reaction smoothly proceeded without any metal catalyst
at ambient temperature making the process environmentally benign. In all of the reactions, a
single new spot appeared on TLC and Knoevenagel adduct (corresponding to 6’{1} or 6{1}) was
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
never obtained in any case.
O
1
2
9{1,1}
Ar = Ph, Ar = Ph (93%)
9{1,2} Ar1 = Ph, Ar2 = 4-Cl-C6H4 (90%)
9{1,3} Ar1= Ph, Ar2 = 4-F-C6H4 (89%)
H
N
N
1
2
9{1,4}
9{1,5}
9{2,1}
Ar = Ph, Ar = 4-MeO-C6H4 (88%)
1
O
N
Ph
Piperidinium acetate
one equivalent
2
Ar = Ph, Ar = 4-Ph-C6H4 (89%)
1
Ar1
8
Ar2
2
Ar = 4-Me-C6H4, Ar = Ph (91%)
N
+
9{2,2} Ar1 = 4-Me-C6H4, Ar2 = 4-Cl-C6H4 (93%)
9{2,3} Ar1 = 4-Me-C6H4, Ar2 = 4-F-C6H4 (90%)
Ethanol, rt, 24 h
N
N
O
Ph
N
1
2
9{2,4}
9{2,5}
Ar = 4-Me-C6H4, Ar = 4-MeO-C6H4 (85%)
1
Ar2
Ar1
2
Ar = 4-Me-C6H4, Ar = 4-Ph-C6H4 (91%)
N3
9
2
O
O
H
H
N
N
N
N
Ph
Ph
8{2}
8{1}
Diversity points in substrate
8
Scheme 2. Synthesis of fused pyrazole-1,2,3-triazolopyridyls library through tandem Knoevenagel condensation-
azide/internal alkyne 1,3-dipolar cycloaddition reaction. Values in parenthesis represent isolated unoptimized yields.
Next we focused our attention towards synthesizing fused pyrazole-1,2,3-triazolopyridyls 9 by
reacting 5-(arylethynyl)-1H-pyrazole-4-carbaldehyde 8 with phenacyl azides 2 using
piperidinium acetate as an additive (Scheme 2). To our delight, substrate 8 smoothly reacted with
phenacyl azides 2 in ethanol at room temperature using one equivalent piperidinium acetate as an
additive leading to high yields of fused pyrazole-1,2,3-triazolopyridyls 9. All the reactions
ACS Paragon Plus Environment
7

Page 9 of 39
ACS Combinatorial Science
1
2
3
4
5
6
7
8
9
proceeded straightforwardly leading to a clean single spot on TLC with no side products. A
series of fused pyrazole-1,2,3-triazolopyridyls 9 were successfully synthesized using the
optimized protocol.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Next we explored the scope of the tandem process using 2-(arylethynyl)benzaldehyde 10 as
substrates. In contrast to indole and pyrazole substrates, the reaction of 2-
(phenylethynyl)benzaldehyde 10{1} with 2-azido-1-(4-fluorophenyl)ethanone 2{3} in ethanol
using one equivalent piperidinium acetate remained incomplete even after 96 h. However,
refluxing the reaction mixture for 24 h led to the complete consumption of both substrates (10{1}
& 2{3}) yielding 11{1,3} (89%) (Scheme 3). Next, a series of fused 1,2,3-triazoloisoquinolines
11 were synthesized by refluxing 2-alkynylaryl aldehydes 10 and phenacyl azides 2 in ethanol
using one equivalent of piperidinium acetate as an additive.
O
H
O
N
1
2
11{1,2}
Ar = Ph, Ar = 4-Cl-C6H4 (85%)
11{1,3} Ar1 = Ph, Ar2 = 4-F-C6H4 (89%)
Ar1 Piperidinium acetate
(one equivalent)
Ar2
10
11{1,4} Ar1 = Ph, Ar2 = 4-MeO-C6H4 (82%)
11{2,2} Ar1 = 4-Me-C6H4, Ar2 = 4-Cl-C6H4 (89%)
N
+
EtOH, reflux, 24 h
1
2
11{2,3}
Ar = 4-Me-C6H4, Ar = 4-F-C6H4 (91%)
2
O
N
Ar1
1
11{2,4}
Ar = 4-Me-C6H4, Ar = 4-MeO-C6H4 (78%)
11{2,5} Ar1 = 4-Me-C6H4, Ar2 = 4-Ph-C6H4 (89%)
N3
Ar2
11
2
Scheme 3. Synthesis of 1,2,3-triazoloisoquinoline library through tandem Knoevenagel condensation-azide/internal
alkyne 1,3-dipolar cycloaddition. Values in parenthesis represent isolated unoptimized yields.
Fused 1,2,3-triazolo-heterocycles 3, 9 & 11 are very interesting heterocycles in terms of their
biological and pharmacological potentials since they bear privileged scaffolds (β-carboline,
pyrazolo-pyridine & isoquinoline) as a part of their chemical structure. Moreover we found that
these fused 1,2,3-triazolo-heterocycles 3, 9 & 11 could be converted to β-carboline 12, pyrazolo-
pyridine 13 & isoquinoline 14 by refluxing the corresponding precursor in acetic acid. Thus,
ACS Paragon Plus Environment
8

ACS Combinatorial Science
Page 10 of 39
1
2
3
4
these new fused heterocycles provide efficient and alternative routes for β-carboline, pyrazolo-
5
6
pyridine & isoquinoline (Scheme 4).
7
8
9
O
O
Cl
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
R''
Cl
O
R'
N
N
N
AcOH
OAc
OAc
N
N
N
N
OAc
Ph
Reflux, 12 h
N
Ph
N
14{2,5}, R'' = 4-biphenyl (95%)
Ph
Bn
R
Corresponding
precursor = 11{2,5}
12{1,2} (95%)
13{1,2} (96%)
Corresponding
precursor = 3{1,2}
Corresponding
9{1,2}
precursor =
Scheme 4. Conversion of fused 1,2,3-triazolo-heterocycles to corresponding β-carboline, pyrazolo-pyridine, and
isoquinoline. Values in parenthesis represent isolated unoptimized yields.
CONCLUSION
An atom economical, tandem, four centred, one pot, two step method has been developed leading
to the formation of structurally novel diverse heterocyclic scaffolds. The generality and scope of
the strategy has been demonstrated on three distinct substrates (indole, pyrazole, and benzene).
Furthermore, efficient conversion of these heterocyles into various other pharmacologically
important β-carboline, pyrazolo-pyridine, and isoquinoline has been illustrated.
EXPERIMENTAL
General information. All the reagents and chemicals were purchased from commercial sources
and used without further any purification. Anhydrous solvents were purchased from Sigma-
Aldrich Company and used without further any purification. Common laboratory solvents (LR
grade) were purchased from domestic suppliers. Analytical thin layer chromatography was
performed with E. Merck silica gel 60 F aluminium plates and visualized under UV 254 nm.
ACS Paragon Plus Environment
9

Page 11 of 39
ACS Combinatorial Science
1
2
3
4
5
6
7
8
9
NMR spectra were measured with Brucker 300, 500, and 600 MHz, and Varian 400 MHz
instruments. Chemical shifts are reported in δ units, parts per million (ppm) downfield from
TMS. Coupling constants (J) are in hertz (Hz) and are unadjusted; therefore, due to limits in
resolution, in some cases there are small differences (<1 Hz) in the measured J value of the same
coupling constant determined from different signals. Splitting patterns are designed as follows: s,
singlet; d, doublet; t, triplet; dd, doublet of doublets; dt, doublet of triplets; tt, triplet of triplets;
m, multiplet; br, broad. IR spectra were recorded on a Perkin–Elmer FT-IR RXI
spectrophotometer and values reported in cm-1. ESI-MS spectra were obtained on a LCQ
Advantage Ion trap mass spectrometer (Finnigan Thermo Fischer Scientific) and High-resolution
mass spectra (ESI-HRMS) were recorded on Agilent 6520 ESI-QTOP mass spectrometer.
Melting points were determined on a Kofler block and are uncorrected. All the new compounds
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1 13
were fully characterized by H NMR, C NMR, Mass-Spectroscopy, IR, and HRMS analysis.
The chromatographic solvents are mentioned as v/v ratios.
General experimental procedure for the synthesis of 2-azido-1-arylethanone 2{1}-2{8}. To a
stirred solution of sodium azide (0.65g, 10 mmol) in 20 mL of acetone-water (2:1, v/v) or DMSO
was added 2-bromo-1-arylethanone (3 mmol) at room temperature. After 2 hours of stirring, the
mixture was poured onto ice-water (100g) and extracted with ethyl acetate (3x50 mL). The
combined organic phases were dried (MgSO4), filtered and evaporated in vacuum to yield
corresponding 2-azido-1-arylethanone. Caution! Organic azides are potentially explosive
substances that can and will decompose with the slightest input of energy from external sources
(heat, light, pressure). They should not be heated too much when concentrating. They should be
stored at low temperature in a refrigerator.
ACS Paragon Plus Environment
10

ACS Combinatorial Science
Page 12 of 39
1
2
3
4
5
6
7
8
9
2-azido-1-phenylethanone 2{1}: 0.440g (91%) of 2{1} was obtained as a yellow oil which
solidifies in the refrigerator starting from 0.597g of phenacyl bromide using DMSO as solvent.
1H NMR (300 MHz, CDCl3) δ: 4.55 (s, 2H), 7.45-7.50 (m, 2H), 7.59 (t, J = 7.4Hz, 1H), 7.87 (d,
J = 7.2Hz, 2H) (Found in accordance with those in literature).14
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2-azido-1-(4-chlorophenyl)ethanone 2{2}: 0.528h (90%) of 2{2} was obtained as a yellow solid
starting from 0.701g of 2-bromo-1-(4-chlorophenyl)ethanone bromide using DMSO as solvent.
1H NMR (500 MHz, CDCl3) δ: 4.53 (s, 2H), 7.47 (d, J = 8.5 Hz, 2H), 7.85 (d, J = 8.5Hz, 2H)
(Found in accordance with those in literature).14
2-azido-1-(4-fluorophenyl)ethanone 2{3}: 0.500g, (93%) of 2{3} was obtained as a yellow solid
stating from 0.651g of 2-bromo-1-(4-fluorophenyl)ethanone bromide using DMSO as solvent. 1H
NMR (300 MHz, CDCl3) δ: 4.54 (s, 2H), 7.15 (t, J = 8.6Hz, 2H), 7.93-7.98 (m, 2H) (Found in
accordance with those in literature).12
2-azido-1-(4-methoxyphenyl)ethanone 2{4}: 0.522g (91%) of 2{4} was obtained as a yellow
solid starting from 0.687g of 2-bromo-1-(4-methoxyphenyl)ethanone using acetone-water (2:1)
1
as solvent. H NMR (500 MHz, CDCl3) δ: 3.88 (s, 3H), 4.51 (s, 2H), 6.95 (d, J = 8.9Hz, 2H),
7.88 (d, J = 8.9Hz, 2H) (Found in accordance with those in literature).15
2-azido-1-(biphenyl-4-yl)ethanone 2{5}: 0.641g (90%) of 2{5} was obtained as a white solid
starting from 0.825g of 1-(biphenyl-4-yl)-2-bromoethanone using acetone-water (2:1) as solvent.
1H NMR (300 MHz, CDCl3) δ: 4.60 (s, 2H), 7.42-7.51 (m, 3H), 7.61-7.64 (m, 2H), 7.71(d, J =
8.5Hz, 2H), 7.97 (d, J = 8.5Hz, 2H) (Found in accordance with those in literature).15
2-azido-1-p-tolylethanone 2{6}: 0.494g (94%) of 2{6} was obtained as a pale yellow solid
starting from 0.639g of 2-bromo-1-p-tolylethanone using acetone-water (2:1) as solvent. 1H
ACS Paragon Plus Environment
11

Page 13 of 39
ACS Combinatorial Science
1
2
3
4
NMR (300 MHz, CDCl3) δ: 2.17 (s, 3H), 4.54 (s, 2H), 7.15-7.21 (m, 2H), 7.93-7.98 (m, 2H)
5
6
(Found in accordance with those in literature).16
7
8
9
2-azido-1-(3-methoxyphenyl)ethanone 2{7}: 0.488g (85%) of 2{7} was obtained as a brown oil
starting from 0.687g of 2-bromo-1-(3-methoxyphenyl)ethanone using acetone-water (2:1) as
solvent. 1H NMR (300 MHz, CDCl3) δ: 3.86 (s, 3H), 4.55 (s, 2H), 7.14-7.18 (m, 1H ), 7.36-7.45
(m, 3H) (Found in accordance with those in literature).17
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2-azido-1-(4-(pyrrolidin-1-yl)phenyl)ethanone 2{8}: 0.608g (88%) of 2{8} was obtained as a
brown solid starting from 0.804g of 2-bromo-1-(4-(pyrrolidin-1-yl)phenyl)ethanone bromide
0
using acetone-water (2:1) as solvent. Mp. 155-156 C; ESI MS (m/z): 231(M+H); IR (KBr, cm-
1
1): 2140, 2103, 1662, 1604, 1549, 1530, 1423, 1397, 1247, 1229; H NMR (300 MHz, CDCl3) δ:
2.00-2.09 (m, 4H), 3.30-3.40 (m, 4H), 4.44 (s, 2H), 6.50 (d, J = 8.9Hz, 2H), 7.77 (d, J = 8.9Hz,
2H); 13C NMR (125 MHz, CDCl3) δ: 25.35, 47.53, 54.04, 110.89, 121.56, 130.23, 151.45,
190.58.
General experimental procedure for the synthesis of 2-(arylethynyl)-1H-indole-3-
carboxyaldehyde 1{1}-1{4}. Compound 1{1}-1{4} were synthesized in three steps as below-
Step 1 (2-oxindole to 2-bromo-1H-indole-3-carboxyaldehyde): To a solution of DMF (3.655g,
50 mmol) in dichloromethane (15 mL) was added drop-wise a solution of phosphorus
oxybromide (11.47g, 40 mmol) in dichloromethane (25 mL) at 0 °C. The white thick mixture
was refluxed during 15 min, and then 2-oxindole (2.66 g, 20 mmol) was added portion-wise. The
mixture was stirred at reflux during 1 h. Next the reaction was quenched by addition of crushed
ice to the media. The mixture was stirred for 20 min and allowed to stand for 10 minutes. Next
the two layers (aqueous-organic) were separated. The aqueous layer was neutralized with solid
ACS Paragon Plus Environment
12

ACS Combinatorial Science
Page 14 of 39
1
2
3
4
5
6
7
8
9
potassium carbonate. The pale yellow precipitate which appeared was filtered and washed with
cold water and purified with silica-gel column chromatography using hexane-ethyl acetate (3:1)
as eluent. Yield- 3.63g (81%) as pale yellow solid, mp 186-188 °C, [ Literature 186 °C].18
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Step
2
(2-bromo-1H-indole-3-carboxyaldehyde
to
1-alkyl-2-bromo-1H-indole-3-
carboxyaldehyde): Sodium hydride [0.40g (60 % dispersion in mineral oil), 10 mmol] was
added to a solution of 2- bromo-1H-indole-3-carboxyaldehyde (2.240g, 10 mmol) in 30 mL of
dry THF at 0-5 °C and stirred for 10 minutes. Next the benzyl bromide (2.052g, 12 mmol) (or
equivalent amount of MeI for methylation) in dry THF (10 mL) was added to it and stirring was
further continued for 6 h at room temperature. When the starting materials were consumed
completely as monitored by TLC, the reaction mixture was concentrated using a vacuum
evaporator to yield a crude product. Pure 1-benzyl-2-bromo-1H-indole-3-carboxyaldehyde was
isolated by purifying the crude through silica gel column chromatography using hexane-ethyl
acetate in increasing polarity as eluent. Characterization data for both the compounds are as
below-
1
1-benzyl-2-bromo-1H-indole-3-carboxyaldehyde: Yield- 2.357g (75%) as white solid, H NMR
(500 MHz, CDCl3) δ: 5.45 (s, 2H), 7.09 (d, J = 7.1Hz, 2H), 7.21-7.35 (m, 6H), 8.32 (d, J =
7.6Hz, 1H), 10.05 (s, 1H) (Found in accordance with those reported in literature).18
1
2-bromo-1-methyl-1H-indole-3-carboxyaldehyde: Yield- 2.023g (85%) as a yellow solid, H
NMR (500 MHz, CDCl3) δ: 3.81 (s, 3H), 7.27-7.37 (m, 3H), 8.30-8.33 (m, 1H), 10.01 (s, 1H)
(Found in accordance with those reported in literature).19
Step 3 (1-benzyl-2-bromo-1H-indole-3-carboxyaldehyde to 1-Benzyl-2-phenylethynyl-1H-
indole-3-carboxyaldehyde 1a): CuI (23.8mg, 0.125 mmol), PdCl2(PPh3)2 (175.5mg, 0.25
ACS Paragon Plus Environment
13

Page 15 of 39
ACS Combinatorial Science
1
2
3
4
mmol), 1-benzyl-2-bromo-1H-indole-3-carboxyaldehyde (1.57g, 5 mmol), were suspended in 10
5
6
mL of anhydrous DMF and 15 mL of Et3N under nitrogen. Next phenyl acetylene (0.562g, 5.5
7
8
9
0
mmol) was added to it and the reaction mixture was stirred overnight at 40 C and then it was
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
diluted in EtOAc (100 mL). Filtration on celite, evaporation of Et3N, DMF and EtOAc under
reduced pressure and purification by flash chromatography on silica gel using hexane-ethyl
acetate in increasing polarity afforded the desired product 1{1} (1.107g, 66%) as pale brown
solid.
1-benzyl-2-(phenylethynyl)-1H-indole-3-carboxyaldehyde 1{1}: 1H NMR (300 MHz, CDCl3) δ:
5.54 (s, 2H), 7.23 (d, J = 6.9Hz, 2H), 7.27-7.34 (m, 6H), 7.37-7.44 (m, 3H), 7.54 (dd, J = 7.8 &
1.5Hz, 2H), 8.35-8.37 (m, 1H), 10.34 (s, 1H) (Found in accordance with those reported in
literature).18
1-benzyl-2-(p-tolylethynyl)-1H-indole-3-carboxyaldehyde 1{2}: 1{2} was also prepared in the
1
same way and on the same scale, 1.345g (77%). H NMR (500 MHz, CDCl3) δ: 2.39 (s, 3H),
5.55 (s, 2H), 7.19 (d, J = 7.9 Hz, 2H), 7.26-7.34 (m, 8H), 7.44 (d, J = 8.1Hz, 2H), 8.34-8.36 (m,
1H), 10.33 (s, 1H) (Found in accordance with those reported in literature).18
1-benzyl-2-(hept-1-ynyl)-1H-indole-3-carboxyaldehyde 1{3}: 1{3} was also prepared in the
same way using 1-benzyl-2-bromo-1H-indole-3-carbaldehyde and 1-heptyne as substrates,
1.318g (80%); light brown oil - ESI MS (m/z): 330(M+H); IR (KBr, cm-1): 2226, 1647, 1612,
1576, 1513, 1495, 1487, 1456, 1430, 1379, 1342, 1213, 1202, 1191; 1H NMR (300 MHz,
CDCl3) δ: 0.86 (t, J = 6.8 Hz, 3H), 1.28-1.46 (m, 4H), 1.68-1.69 (m, 2H), 2.52 (t, J = 7.6Hz, 2H),
5.45 (s, 2H), 7.15-7.37 (m, 8H), 8.30-8.33 (m, 1H), 10.20 (s, 1H); 13C NMR (125 MHz, CDCl3)
δ: 13.81, 19.67, 22.02, 27.75, 30.92, 48.19, 69.28, 103.81, 110.23, 119.59, 121.94, 123.25,
ACS Paragon Plus Environment
14

ACS Combinatorial Science
Page 16 of 39
1
2
3
4
5
6
124.51, 124.66, 126.61, 127.74, 128.73, 132.90, 135.95, 136.44, 185.37; HRMS calculated for
C23H24ON (M+H): 330.18524; found 330.18500.
7
8
9
1-benzyl-2-(hept-1-ynyl)-1H-indole-3-carboxyaldehyde 1{4}: 1{4} was prepared in the same
way using 1-methyl-2-bromo-1H-indole-3-carbaldehyde and 1-heptyne as substrates, 0.925g
(73%), %); light brown oil. ESI MS (m/z): 254(M+H); IR (KBr, cm-1): 2231, 1651, 1609, 1574,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
1513, 1465, 1410, 1382, 1330, 1254, 1127; H NMR (500 MHz, CDCl3) δ: 0.93 (t, J = 7.3Hz,
3H), 1.35-1.51 (m, 4H), 1.67-1.73 (m, 2H), 2.57 (t, J = 7.0Hz, 2H), 3.80 (s, 3H), 7.26-7.35 (m,
3H), 8.28 (d, J = 7.3Hz, 1H), 10.13 (s, 1H); 13C NMR (125 MHz, CDCl3) δ: 13.91, 19.74, 22.09,
27.91, 30.89, 31.05, 69.20, 103.64, 109.51, 119.33, 121.92, 123.22, 124.27, 124.53, 133.16,
137.01, 185.24; HRMS calculated for C17H20ON (M+H): 254.15394; found 254.15363.
General experimental procedure for the synthesis of 3-methyl-1-phenyl-5-(arylethynyl)-1H-
pyrazole-4-carboxyaldehyde 8{1}-8{2}. Compound 8{1} and 8{2} were synthesized in three
steps-
Step 1 [Phenyl hydrazine to 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one]: Phenyl hydrazine
(9.73g, 90 mmol) was taken in 50 mL of glacial acetic acid and methyl acetoacetate (10.45g, 90
mmol) was added to it and stirred at reflux for 3 h. Thereafter the reaction mixture was
evaporated to dryness and to the residue was extracted with water (50 mL) and EtOAc (50 mL).
The organic layer was separated whereas the aqueous layer was further extracted with EtOAc (2
x 50 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated over
reduced pressure to afford pure 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one as a white solid
(10.975g, 70%). Mp. 127-128 °C [Literature 127.5 to 128.5 °C].20
ACS Paragon Plus Environment
15

Page 17 of 39
ACS Combinatorial Science
1
2
3
4
5
6
7
8
9
Step 2 [3-methyl-1-phenyl-1H-pyrazol-5(4H)-one to 5-chloro-3-methyl-1-phenyl-1H-
pyrazole-4-carboxyaldehyde]: To a stirred solution of 5-methyl-2-phenyl-2,4-dihydro-3H-
pyrazol-3-one (10 g, 57 mmol) in dry DMF (100 mL), POCl3 (13.4 mL,144 mmol) was added
drop-wise at 0 °C. After addition, the reaction was continued at 100 0C for 6 h. Then the reaction
mixture was poured into 150 g of ice-200 mL water and neutralized with saturated aqueous
solution of NaHCO3. Thereafter EtOAc (400 mL) was added to it and organic layer was
separated whereas the aqueous layer was further extracted with EtOAc (2 x 200 mL). The pooled
organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure.
Purification of the crude product by column chromatography over silica gel (EtOAc/ hexanes,
1:9) furnished pure product as a white solid (9.0 g, 71%). 1H NMR (500 MHz, CDCl3) δ: 2.54 (s,
3H), 7.46-7.54 (m, 5H), 9.97 (s, 1H) (Found in accordance with those in literature).21
Step 3 [5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde to 3-methyl-1-phenyl-5-
(phenylethynyl)-1H-pyrazole-4-carboxyaldehyde]: Triethylamine (5.06g, 50 mmol), phenyl
acetylene (1.53g, 15 mmol), (PPh3) 2Pd Cl2 (701 mg, 1 mmol) and CuI (380 mg, 2 mmol) were
added under nitrogen to a solution of 5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde
(2.21g, 10 mmol) in dry DMF (20 mL) and the reaction mixture was stirred at 80 °C for 4 h.
DMF was evaporated under reduced pressure. The residue was dissolved in dichloromethane (20
mL), water (40 mL) was added, and the mixture was extracted with dichloromethane (3 x 40
mL). The organic layers were combined, washed with brine and dried with Na2SO4. The solvent
was evaporated and the residue was purified by silica-gel column chromatography to yield 2.12 g
(74%) of 8{1}.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment
16

ACS Combinatorial Science
Page 18 of 39
1
2
1
3
4
5
6
7
8
9
3-methyl-1-phenyl-5-(phenylethynyl)-1H-pyrazole-4-carboxyaldehyde 8{1}: H NMR (300
MHz, CDCl3) δ: 2.59 (s, 3H), 7.35-7.55 (m, 8H), 7.82 (d, J = 7.5Hz, 2H), 10.17 (s, 1H) (Found
in accordance with those in literature).22
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3-methyl-1-phenyl-5-(p-tolylethynyl)-1H-pyrazole-4-carboxyaldehyde 8{2}: 8{2} was also
prepared in the same way and on the same scale, 1.952g (65%) - 1H NMR (300 MHz, CDCl3) δ:
2.38 (s, 3H), 2.58 (s, 3H), 7.17 (d, J = 7.9 Hz, 2H), 7.36-7.54 (m, 5H), 7.81 (d, J = 7.5Hz, 2H),
10.16 (s, 1H) (Found in accordance with those in literature).22
4.5. General experimental procedure for the synthesis of 2-(arylethynyl)benzaldehyde
11{1}-11{2}: (Ph3P)2PdCl2 (152 mg, 0.22 mmol) and CuI (21 mg, 0.11 mmol) were added to a
solution of 2-bromobenzaldehyde (2.00 g, 10.81 mmol) and phenylacetylene (1.32 g, 12.97
mmol) in triethylamine (45 mL). Next the reaction mixture was heated under nitrogen
atmosphere at 50 °C until completion (TLC). The reaction mixture was concentrated under
reduced pressure and purified by silica-gel column chromatography using n-hexane/ethyl acetate
(24:1 v/v) as eluent to give 11{1} (1.70g, 77%) as a yellow oil.
2-(phenylethynyl)benzaldehyde 11{1}: 1H NMR (500 MHz, CDCl3) δ: 7.37– 7.41 (m, 3H), 7.44
(t, J = 7.5 Hz, 1H), 7.52–7.60 (m, 3H), 7.64 (d, J = 7.6 1H), 7.95 (dd, J = 7.8 & 0.9 Hz, 1H),
10.66 (s, 1H) (Found in accordance with those in literature).23
2-(p-tolylethynyl)benzaldehyde 11{2}: In the same way, 11{2} was also prepared on the same
scale, 1.55g, (65%) - 1H NMR (500 MHz, CDCl3) δ: 2.39 (s, 3H), 7.19 (d, J = 7.9 Hz, 2H), 7.42-
7.47 (m, 3H), 7.56 (dt, J = 7.5 & 1.2 Hz, 1H), 7.63 (d, J = 7.5Hz, 1H), 7.94 (dd, J = 7.8 & 0.9
Hz, 1H), 10.66 (s, 1H) (Found in accordance with those in literature).24
ACS Paragon Plus Environment
17

Page 19 of 39
ACS Combinatorial Science
1
2
3
4
General experimental procedure for the synthesis of fused 1,2,3-triazolo-β-
5
6
7
8
9
carbolines 3. To a stirred solution of 1{1}-1{4} (0.20 mmol) and 2-azido-1-(aryl)ethanone 2{1}-
2{8} (0.20 mmol) in ethanol (2.0 mL) was added 0.20 mmol of piperidinium acetate and stirring
was further continued till complete consumption of the starting substrates (TLC). Next ethanol
was evaporated in vacuum and residue was extracted with chloroform/water (15 mL each). The
organic layer was separated, dried over anhydrous Na2SO4 and evaporated to yield crude which
was purified through silica gel column chromatography using ethyl acetate/hexane as eluent in
increasing polarity.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Compound 3{1,1}: Mp. 196-198 °C; 84mg (88%) of 3{1,1} was obtained as a light yellow solid
starting from 67mg of 1{1}: ESI MS (m/z): 479(M+H); IR (KBr, cm-1): 1699, 1624, 1511, 1497,
1
1466, 1397, 1345, 1281, 1250, 1203; H NMR (300 MHz, CDCl3) δ: 5.27 (s, 2H), 6.49 (d, J =
7.0Hz, 2H), 7.09-7.17 (m, 3H), 7.21-7.28 (m, 3H), 7.31-7.45 (m, 5H), 7.51 (m, 2H), 7.64 (m,
13
1H), 7.97-8.03 (m, 4H); C NMR (125 MHz, CDCl3) δ: 50.00, 111.58, 114.44, 115.50, 119.84,
122.05, 123.28, 123.71, 125.54, 126.28, 127.40, 127.60, 128.37, 128.48, 128.67, 128.95, 130.04,
130.40, 130.92, 132.92, 133.57, 135.82, 136.99, 137.31, 140.42, 188.17; HRMS calculated for
C32H23ON4 (M+H): 479.18719 found 479.18609.
Compound 3{1,2}: Mp. 126-128 °C; 85mg (83%) of 3{1,2} was obtained as a yellow solid
starting from 67mg of 1{1}: ESI MS (m/z): 513(M+H); IR (KBr, cm-1): 1657, 1624, 1586, 1543,
1
1508, 1496, 1485, 1399, 1278, 1253, 1234, 1208; H NMR (500 MHz, CDCl3) δ: 5.28 (s, 2H),
6.50 (d, J = 7.3Hz, 2H), 7.11-7.19 (m, 3H), 7.22-7.28 (m, 3H), 7.32-7.45 (m, 5H), 7.49 (d, J =
8.5Hz, 2H), 7.90 (d, J = 8.5Hz, 2H), 8.03 (s, 1H), 8.04 (d, J = 8.0Hz, 1H); 13C NMR (125 MHz,
CDCl3) δ: 50.00, 111.59, 114.56, 115.54, 119.82, 122.14, 123.19, 123.62, 125.50, 126.37,
127.20, 127.40, 128.37, 128.47, 128.99, 130.32, 131.00, 131.26, 132.35, 135.36, 135.72, 137.37,
ACS Paragon Plus Environment
18

ACS Combinatorial Science
Page 20 of 39
1
2
3
4
5
6
139.94, 140.39, 186.99; HRMS calculated for C32H22ON4Cl (M+H): 513.14767 found
513.14795.
7
8
9
Compound 3{1,3}: Mp. 200-202 °C; 90mg (91%) of 3{1,3} was obtained as a yellow solid
starting from 67mg of 1{1}: ESI MS (m/z): 497(M+H); IR (KBr, cm-1): 1673, 1644, 1622, 1596,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
1567, 1504, 1299, 1278, 1252, 1232, 1215; H NMR (300 MHz, CDCl3) δ: 5.28 (s, 2H), 6.50 (d,
13
J = 6.9Hz, 2H), 7.10-7.26 (m, 8H), 7.32-7.45 (m, 5H), 7.98-8.06 (m, 4H); C NMR (100 MHz,
CDCl3) δ: 50.00, 111.63, 114.20, 115.55, 115.84, 116.08, 119.86, 122.14, 123.23, 125.54,
126.39, 127.45, 128.41, 129.03, 130.38, 130.93, 132.43, 132.63, 132.75, 133.31, 135.80, 137.37,
140.42, 164.80, 167.35, 186.80; HRMS calculated for C32H22ON4F (M+H): 497.17722 found
497.17666.
Compound 3{1,4}: Mp. 123-125 °C; 87mg (86%) of 3{1,4} was obtained as a pale yellow solid
starting from 67mg of 1{1}: ESI MS (m/z): 509(M+H); IR (KBr, cm-1): 1621, 1598, 1510, 1468,
1
1417, 1254; H NMR (300 MHz, CDCl3) δ: 3.90 (s, 3H), 5.27 (s, 2H), 6.49 (d, J = 6.8Hz, 2H),
6.98 (d, J = 8.3Hz, 2H), 7.05-7.31 (m, 6H), 7.32-7.40 (m, 3H), 7.43 (d, J = 7.6Hz, 2H), 7.95-8.04
13
(m, 4H); C NMR (125 MHz, CDCl3) δ: 49.93, 55.55, 111.50, 113.09, 113.98, 115.58, 119.80,
121.89, 123.21, 123.70, 125.53, 126.17, 127.33, 127.91, 128.34, 128.44, 128.89, 129.52, 130.38,
130.50, 132.56, 135.90, 137.16, 140.35, 164.17, 186.89; HRMS calculated for C33H25O2N4
(M+H): 509.19720 found 509.19607.
Compound 3{1,5}: Mp. 209-211 °C; 100mg (90%) of 3{1,5} was obtained as a yellow solid
starting from 67mg of 1{1}: ESI MS (m/z): 555(M+H); IR (KBr, cm-1): 1661, 1601, 1624, 1509,
1
1496, 1485, 1467, 1450, 1396, 1278, 1255; H NMR (500 MHz, CDCl3) δ: 5.28 (s, 2H), 6.51 (d,
J = 7.3Hz, 2H), 7.11-7.18 (m, 3H), 7.22-7.26 (m, 3H), 7.33-7.50 (m, 8H), 7.66 (d, J = 7.5Hz,
ACS Paragon Plus Environment
19

Page 21 of 39
ACS Combinatorial Science
1
2
13
2H), 7.73 (d, J = 8.2H, 2H), 8.03-8.07 (m, 4H); C NMR (75 MHz, CDCl3) δ: 50.07, 110.43,
3
4
5
6
7
8
111.66, 114.33, 115.64, 116.95, 119.95, 122.13, 123.35, 123.79, 125.62, 126.38, 127.39, 127.48,
128.38, 128.47, 128.56, 129.02, 130.19, 130.48, 130.74, 132.57, 135.69, 135.92, 137.40, 139.85,
140.49, 146.42, 187.85; HRMS calculated for C38H27ON4 (M+H): 555.21794 found 555.21720.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Compound 3{1,6}: Mp. 174-176 °C; 79mg (80%) of 3{1,6} was obtained as a light yellow solid
starting from 67mg of 1{1}: ESI MS (m/z): 493(M+H); IR (KBr, cm-1): 1658, 1624, 1604, 1573,
1
1496, 1469, 1451, 1362, 1266, 1251, 1233; H NMR (300 MHz, CDCl3) δ: 2.47 (s, 3H), 5.27 (s,
2H), 6.49 (d, J = 6.8Hz, 2H), 7.00-7.27 (m, 6H), 7.30-7.40 (m, 5H), 7.43 (d, J = 7.6Hz, 2H), 7.89
13
(d, J = 7.6Hz, 2H), 7.98 (s, 1H), 8.02 (d, J = 6.8Hz, 1H); C NMR (75 MHz, CDCl3) δ: 21.32,
50.04, 111.57, 114.48, 115.35, 119.80, 122.01, 123.29, 123.73, 125.50, 126.20, 127.34, 127.57,
128.35, 128.65, 129.02, 129.40, 130.01, 130.16, 131.06, 133.53, 135.95, 136.99, 138.80, 140.43,
188.20; HRMS calculated for C33H25ON4 (M+H): 493.20229; found 493.20186.
Compound 3{1,7}: Mp. 89-91 °C; 83mg (82%) of 3{1,7} was obtained as a yellow solid starting
from 67mg of 1{1}: ESI MS (m/z): 509(M+H); IR (KBr, cm-1): 1660, 1622, 1595, 1495, 1485,
1
1466, 1428, 1395, 1268, 1240; H NMR (300 MHz, CDCl3) δ: 3.88 (s, 3H), 5.27 (s, 2H), 6.49 (d,
J = 6.8Hz, 2H), 7.07-7.26 (m, 7H), 7.31-7.45 (m, 6H), 7.49 (d, J = 7.6Hz, 1H), 7.59 (s, 1H),
8.00-8.03 (m, 2H); 13C NMR (75 MHz, CDCl3) δ: 49.95, 55.48, 111.54, 114.01, 114.42, 115.38,
119.80, 120.15, 122.01, 122.86, 123.21, 125.50, 126.23, 127.34, 128.33, 128.44, 128.91, 129.58,
130.33, 130.86, 132.46, 135.77, 137.29, 138.25, 140.37, 159.80, 187.87; HRMS calculated for
C33H25O2N4 (M+H): 509.19720 found 509.19758.
Compound 3{1,8}: Mp. 129-131 °C; 88mg (80%) of 3{1,8} was obtained as a yellow solid
starting from 67mg of 1{1}: ESI MS (m/z): 548(M+H); IR (KBr, cm-1): 1633, 1590, 1543, 1530,
ACS Paragon Plus Environment
20

ACS Combinatorial Science
Page 22 of 39
1
2
1
3
1505, 1495, 1463, 1316, 1237; H NMR (300 MHz, CDCl3) δ: 2.00-2.13 (m, 4H), 3.30-3.47 (m,
4H), 5.25 (s, 2H), 6.48 (d, J = 6.6Hz, 2H), 6.56 (d, J = 8.9Hz, 2H), 7.08-7.16 (m, 3H), 7.20-7.26
(m, 3H), 7.30-7.40 (m, 3H), 7.43 (d, J = 7.0Hz, 2H), 7.87 (s, 1H), 7.93 (d, J = 8.9Hz, 2H), 8.00
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
(d, J = 8.0Hz, 1H); C NMR (75 MHz, CDCl3) δ: 25.45, 47.68, 49.92, 111.07, 111.45, 111.57,
115.79, 119.86, 121.69, 123.32, 123.64, 125.62, 126.03, 127.34, 128.38, 128.50, 128.85, 130.54,
132.11, 132.89, 133.04, 136.18, 140.39, 151.80, 186.22; HRMS calculated for C36H30ON5
(M+H): 548.24449 found 548.24347.
Compound 3{2,1}: Mp. 197-198 °C; 80mg (81%) of 3{2,1} was obtained as a light yellow solid
starting from 70mg of 1{2}: ESI MS (m/z): 493(M+H); IR (KBr, cm-1): 1669, 1595, 1549, 1519,
1
1485, 1469, 1447, 1395, 1350, 1204; H NMR (300 MHz, CDCl3) δ: 2.36 (s, 3H), 5.28 (s, 2H),
6.52 (d, J = 6.8Hz, 2H), 6.99 (d, J = 7.7Hz, 2H), 7.10-7.17 (m, 3H), 7.22-7.40 (m, 5H), 7.50 (t, J
13
= 7.6Hz, 2H), 7.63 (t, J = 7.3Hz, 1H), 7.97-8.03 (m, 4H); C NMR (75 MHz, CDCl3) δ: 21.41,
50.13, 111.66, 114.57, 115.44, 119.90, 122.10, 123.38, 123.82, 125.59, 126.29, 127.42, 127.66,
128.44, 128.73, 129.11, 129.49, 130.10, 130.25, 133.62, 136.04, 137.08, 138.89, 140.52, 188.28;
HRMS calculated for C33H25ON4 (M+H): 493.20229 found 493.20186.
Compound 3{2,2}: Mp. 184-186 °C; 84mg (80%) of 3{2,2} was obtained as a yellow solid
starting from 70mg of 1{2}: ESI MS (m/z): 527(M+H); IR (KBr, cm-1): 1681, 1660, 1645, 1633,
1599, 1556, 1531, 1519, 1496, 1485, 1397, 1279, 1267, 1251, 1232; 1H NMR (300 MHz,
CDCl3) δ: 2.36 (s, 3H), 5.28 (s, 2H), 6.52 (d, J = 7.0Hz, 2H), 6.99 (d, J = 7.6Hz, 2H), 7.10-7.19
(m, 3H), 7.24-7.40 (m, 5H), 7.48 (d, J = 8.5Hz, 2H), 7.88 (d, J = 8.5Hz, 2H), 8.02-8.05 (m, 2H);
13C NMR (75 MHz, CDCl3) δ: 21.41, 50.20, 111.71, 114.65, 115.53, 119.89, 122.22, 123.32,
123.76, 125.56, 126.41, 127.45, 128.44, 129.11, 129.34, 130.22, 131.35, 135.48, 135.95, 137.58,
ACS Paragon Plus Environment
21

Page 23 of 39
ACS Combinatorial Science
1
2
3
4
5
6
139.97, 140.02, 140.52, 187.15; HRMS calculated for C33H24ON4Cl (M+H): 527.16332 found
527.16341.
7
8
9
Compound 3{2,5}: Mp. 113-115 °C; 94mg (83%) of 3{2,5} was obtained as a yellow solid
starting from 70mg of 1{2}: ESI MS (m/z): 569(M+H); IR (KBr, cm-1): 1693, 1660, 1644, 1633,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
1601, 1556, 1538, 1495, 1485, 1469, 1393, 1278, 1180; H NMR (300 MHz, CDCl3) δ: 2.36 (s,
3H), 5.28 (s, 2H), 6.53 (d, J = 6.8Hz, 2H), 7.00 (d, J = 7.7Hz, 2H), 7.11-7.18 (m, 3H), 7.25-7.49
13
(m, 8H), 7.66 (d, J = 7.0Hz, 2H), 7.73 (d, J = 8.3Hz, 2H), 8.03-8.07 (m, 4H); C NMR (125
MHz, CDCl3) δ: 21.26, 50.09, 111.61, 114.21, 115.50, 119.86, 122.03, 123.36, 123.77, 125.54,
126.24, 126.88, 127.33, 127.77, 128.30, 128.39, 128.95, 129.05, 129.44, 130.21, 130.66, 131.07,
131.74, 135.68, 136.00, 137.42, 138.83, 139.83, 140.48, 146.33, 187.84; HRMS calculated for
C39H29ON4 (M+H): 569.23359 found 569.23323.
Compound 3{2,6}: Mp. 196-198 °C; 82mg (81%) of 3{2,6} was obtained as a pale yellow solid
starting from 70mg of 1{2}: ESI MS (m/z): 507(M+H); IR (KBr, cm-1): 1698, 1693, 1681, 1667,
1
1651, 1644, 1633, 1621, 1538, 1519, 1495, 1469, 1452, 1434, 1395, 1351, 1257, 1235, 1205; H
NMR (300 MHz, CDCl3) δ: 2.36 (s, 3H), 2.47 (s, 3H), 5.28 (s, 2H), 6.52 (d, J = 6.8Hz, 2H), 7.00
(d, J = 7.7Hz, 2H), 7.10-7.17 (m, 3H), 7.24-7.38 (m, 7H), 7.88 (d, J = 8.1 Hz, 2H), 7.97 (s, 1H),
13
8.00 (d, J = 7.2Hz, 1H); C NMR (75 MHz, CDCl3) δ: 21.32, 50.04, 111.57, 114.48, 115.35,
119.80, 122.01, 123.29, 123.73, 125.50, 126.20, 127.34, 127.57, 128.35, 128.65, 129.02, 129.40,
130.01, 130.16, 131.06, 133.53, 135.95, 136.99, 138.80, 140.43, 188.20; HRMS calculated for
C34H27ON4 (M+H): 507.21794 found 507.21685.
Compound 3{3,2}: Mp. 116-119 °C; 81mg (80%) of 3{3,2} was obtained as a pale yellow solid
starting from 66mg of 1{3}: ESI MS (m/z): 507(M+H); IR (KBr, cm-1): 1660, 1620, 1604, 1586,
ACS Paragon Plus Environment
22

ACS Combinatorial Science
Page 24 of 39
1
2
1537, 1495, 1487, 1470, 1452, 1401, 1360, 1278, 1251, 1229, 1205; 1H NMR (300 MHz,
CDCl3) δ: 0.81 (t, J = 6.8Hz, 3H), 1.09-1.27 (m, 4H), 1.75-1.88 (m, 2H), 3.02 (t, J = 7.6Hz, 2H),
5.95 (s, 2H), 7.07-7.10 (m, 2H), 7.30-7.46 (m, 8H), 7.80 (d, J = 8.3Hz, 2H), 7.97 (s, 1H), 8.03 (d,
J = 8.3Hz, 1H); 13C NMR (75 MHz, CDCl3) δ: 13.95, 22.23, 27.99, 29.85, 31.54, 49.76, 110.94,
114.03, 114.62, 119.76, 122.18, 123.15, 123.33, 125.41, 126.25, 127.52, 127.99, 128.94, 129.24,
131.10, 131.50, 135.52, 135.93, 136.74, 139.79, 140.15, 187.28; HRMS calculated for
C31H28ON4Cl (M+H): 507.19462 found 507.19406.
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Compound 3{3,6}: Mp. 129-130 °C; 79mg (81%) of 3{3,6} was obtained as a pale yellow solid
starting from 66mg of 1{3}: ESI MS (m/z): 487(M+H); IR (KBr, cm-1): 1655, 1619, 1604, 1533,
1
1493, 1470, 1451, 1398, 1362, 1332, 1261, 1237 ; H NMR (300 MHz, CDCl3) δ: 0.83 (t, J = 6.8
Hz, 3H), 1.16-1.34 (m, 4H), 1.76-1.90 (m, 2H), 2.46 (s, 3H), 3.04 (t, J = 7.6Hz, 2H), 5.97 (s,
2H), 7.09 (d, J = 6.8Hz, 2H), 7.28-7.47 (m, 8H), 7.82 (d, J = 7.6Hz, 2H), 7.93 (s, 1H), 8.01 (d, J
13
= 7.6Hz, 1H); C NMR (75 MHz, CDCl3) δ: 14.02, 21.85, 22.34, 28.07, 30.05, 31.59, 49.75,
110.96, 113.53, 114.59, 119.77, 122.04, 123.21, 123.44, 125.47, 126.14, 128.00, 129.26, 129.37,
130.16, 131.26, 134.46, 136.12, 136.68, 140.14, 144.56, 188.20; HRMS calculated for
C32H31ON4 (M+H): 487.24924 found 487.25027.
Compound 3{4,2}: Mp. 184-185 °C; 67mg (78%) of 3{4,2} was obtained as a pale yellow solid
starting from 51mg of 1{4}: ESI MS (m/z): 431(M+H); IR (KBr, cm-1): 1649, 1623, 1605, 1585,
1
1500, 1485, 1397, 1247, 1182; H NMR (300 MHz, CDCl3) δ: 0.90 (t, J = 6.8 Hz, 3H), 1.34-
1.62 (m, 4H), 1.91-2.08 (m, 2H), 3.34 (t, J = 7.6Hz, 2H), 4.29 (s, 3H), 7.28-7.45 (m, 3H), 7.52-
7.60 (m, 2H), 7.74 (d, J = 8.3Hz, 2H), 7.89 (s, 1H), 7.96 (d, J = 8.3Hz, 1H); 13C NMR (75 MHz,
CDCl3) δ: 14.02, 22.50, 28.78, 29.88, 31.73, 33.62, 110.14, 114.19, 114.36, 119.72, 121.84,
ACS Paragon Plus Environment
23

Page 25 of 39
ACS Combinatorial Science
1
2
3
4
5
6
122.80, 123.42, 126.05, 127.10, 128.89, 131.04, 131.38, 135.57, 136.64, 139.68, 140.48, 187.26;
HRMS calculated for C25H24ON4Cl (M+H): 431.16332; found 431.16326.
7
8
9
Compound 3{4,6}: Mp. 128-129 °C; 66mg (80%) of 3{4,6} was obtained as a pale yellow solid
starting from 51mg of 1{4}: ESI MS (m/z): 411(M+H); IR (KBr, cm-1): 1650, 1623, 1605, 1573,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
1501, 1455, 1380, 1248, 1184; H NMR (300 MHz, CDCl3) δ: 0.90 (t, J = 6.8 Hz, 3H), 1.36-
1.54 (m, 4H), 1.90-2.01 (m, 2H), 2.43 (s, 3H), 3.35 (t, J = 7.6Hz, 2H), 4.28 (s, 3H), 7.25 (d, J =
8.3Hz, 2H), 7.33-7.37 (m, 1H), 7.49-7.57 (m, 2H), 7.75 (d, J = 8.3Hz, 2H), 7.84 (s, 1H), 7.94 (d,
13
J = 7.6Hz, 1H); C NMR (75 MHz, CDCl3) δ: 14.02, 21.74, 22.50, 28.77, 29.97, 31.73, 33.56,
110.08, 113.52, 114.26, 119.64, 121.61, 122.79, 123.44, 125.85, 127.62, 129.26, 129.99, 131.07,
134.47, 136.48, 140.43, 144.35, 188.10; HRMS calculated for C26H27ON4 (M+H): 411.21794
found 411.21741.
General experimental procedure for the synthesis of fused pyrazole-1,2,3-triazolopyridyls
9{1,1}-9{2,5}. To a stirred solution of 8{1}/8{2} (0.20 mmol) and 2-azido-1-(aryl)ethanone 2{1}-
2{5} (0.20 mmol) in ethanol (2.0 mL) was added 0.20 mmol of piperidinium acetate and stirring
was further continued for 24 h till complete consumption of the starting substrates (TLC). Next
ethanol was evaporated in vacuum and residue was extracted with chloroform/water (15 mL
each). The organic layer was separated, dried over anhydrous Na2SO4 and evaporated to yield
crude which was purified through silica gel column chromatography using ethyl acetate/hexane
as eluent in increasing polarity.
Compound 9{1,1}: Mp. 192-193 °C; 80mg (93%) of 9{1,1} was obtained as a white solid
starting from 57mg of 8{1}: ESI MS (m/z): 430(M+H); IR (KBr, cm-1): 1667, 1595, 1580, 1558,
1530, 1512, 1501, 1459, 1447, 1398, 1318, 1302, 1285, 1251, 1222; 1H NMR (300 MHz,
ACS Paragon Plus Environment
24

ACS Combinatorial Science
Page 26 of 39
1
2
3
4
CDCl3) δ: 2.64 (s, 3H), 6.85-7.12 (m, 6H), 7.16-7.32 (m, 4H), 7.37-7.55 (m, 3H), 7.64 (t, J =
5
6
13
7.2Hz, 1H), 7.93 (d, J = 7.6Hz, 2H); C NMR (125 MHz, CDCl3) δ: 11.76, 112.44, 118.20,
7
8
9
121.43, 123.81, 127.74, 127.75, 128.29, 128.53, 128.74, 129.71, 129.81, 130.59, 131.15, 133.94,
136.33, 139.42, 139.60, 146.59, 187.97; HRMS calculated for C27H20ON5 (M+H): 430.16624
found 430.16646.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Compound 9{1,2}: Mp. 206-206 °C; 84mg (90%) of 9{1,2} was obtained as a light yellow solid
starting from 57mg of 8{1}: ESI MS (m/z): 464(M+H); IR (KBr, cm-1): 1661, 1633, 1587, 1529,
1
1496, 1461, 1320, 1303, 1283, 1275, 1258; H NMR (500 MHz, CDCl3) δ: 2.65 (s, 3H), 6.91-
6.99 (m, 4H), 7.00-7.10 (m, 2H), 7.18 (d, J = 7.5Hz, 2H), 7.22 (d, J = 7.6Hz, 2H), 7.48 (d, J =
8.2Hz, 2H), 7.53 (s, 1H), 7.86 (d, J = 8.4Hz, 2H); 13C NMR (125 MHz, CDCl3) δ: 11.79, 112.70,
118.24, 121.41, 123.83, 127.80, 127.84, 128.30, 128.56, 129.13, 129.43, 130.67, 131.05, 131.16,
134.79, 139.54, 139.57, 140.43, 146.70, 186.87; HRMS calculated for C27H19ON5Cl (M+H):
464.12726 found 464.12842.
Compound 9{1,3}: Mp. 219-220 °C; 80mg (90%) of 9{1,3} was obtained as a white solid
starting from 57mg of 8{1}: ESI MS (m/z): 448(M+H); IR (KBr, cm-1): 1666, 1634, 1594, 1558,
1
1530, 1499, 1461, 1285, 1257; H NMR (500 MHz, CDCl3) δ: 2.65 (s, 3H), 6.89-7.00 (m, 4H),
13
7.02-7.10 (m, 2H), 7.17-7.25 (m, 6H), 7.51 (s, 1H), 7.95-7.98 (m, 2H); C NMR (125 MHz,
CDCl3) δ: 11.76, 112.31, 115.94, 116.12, 118.22, 121.41, 123.82, 127.78, 128.73, 128.53,
129.52, 130.58, 131.06, 132.52, 132.61, 132.71, 139.48, 139.58, 146.60, 165.18, 167.23, 186.53;
HRMS calculated for C27H19ON5F (M+H): 448.15681 found 448.15739.
Compound 9{1,4}: Mp. 174-176 °C; 81mg (88%) of 9{1,4} was obtained as a light yellow solid
starting from 57mg of 8{1}: ESI MS (m/z): 460(M+H); IR (KBr, cm-1): 1647, 1626, 1596, 1569,
ACS Paragon Plus Environment
25

Page 27 of 39
ACS Combinatorial Science
1
2
1
3
4
1525, 1445, 1422, 1304, 1258, 1213; H NMR (500 MHz, CDCl3) δ: 2.64 (s, 3H), 3.90 (s, 3H),
5
6
13
6.90-7.08 (m, 8H), 7.16-7.25 (m, 4H), 7.44 (s, 1H), 7.94 (d, J = 8.5Hz, 2H); C NMR (125
7
8
9
MHz, CDCl3) δ: 11.77, 55.58, 111.28, 114.08, 118.28, 121.46, 123.83, 127.75, 128.30, 128.44,
128.52, 129.03, 130.05, 130.41, 131.24, 132.48, 139.38, 139.68, 146.39, 164.42, 186.57; HRMS
calculated for C28H22O2N5 (M+H): 460.17680 found 460.17772.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Compound 9{1,5}: Mp. 186-188 °C; 90mg (89%) of 9{1,5} was obtained as a light yellow solid
starting from 57mg of 8{1}: ESI MS (m/z): 506(M+H); IR (KBr, cm-1): 1658, 1632, 1599, 1530,
1
1512, 1496, 1461, 1445, 1317, 1301, 1273, 1257, 1228; H NMR (500 MHz, CDCl3) δ: 2.66 (s,
13
3H), 6.96-8.02(m, 20H); C NMR (125 MHz, CDCl3) δ: 11.76, 112.32, 118.24, 121.42, 123.52,
123.78, 127.23, 127.33, 127.72, 128.26, 128.34, 128.48, 128.90, 129.76, 130.06, 130.48, 131.13,
134.95, 139.41, 139.58, 146.58, 146.61, 187.50; HRMS calculated for C33H24ON5 (M+H):
506.19754 found 506.19907.
Compound 9{2,1}: Mp. 204-204 °C; 81mg (91%) of 9{2,1} was obtained as a white solid
starting from 60mg of 8{2}: ESI MS (m/z): 444(M+H); IR (KBr, cm-1): 1670, 1625, 1614, 1597,
1
1527, 1499, 1463, 1447, 1377, 1320, 1303, 1284, 1240; H NMR (300 MHz, CDCl3) δ: 2.24 (s,
3H), 2.63 (s, 3H), 6.72 (d, J = 7.7Hz, 2H), 6.92-6.97 (m, 2H), 7.00-7.09 (m, 3H), 7.19 (d, J =
7.6Hz, 2H),7.49 (s, 1H), 7.51 (d, J = 7.7Hz, 2H), 7.63-7.68 (m, 1H), 7.93 (d, J = 7.2Hz, 2H); 13C
NMR (125 MHz, CDCl3) δ: 11.77, 21.15, 112.39, 118.10, 121.43, 123.86, 127.72, 128.09,
128.22, 128.45, 128.73, 129.72, 129.89, 130.70, 133.92, 136.38, 137.50, 139.55, 139.73, 146.55,
188.04; HRMS calculated for C28H22ON5 (M+H): 444.18189 found 444.18204.
Compound 9{2,2}: Mp. 192-194 °C; 89mg (93%) of 9{2,2} was obtained as a white solid
starting from 60mg of 8{2}: ESI MS (m/z): 478(M+H); IR (KBr, cm-1): 1660, 1633, 1530, 1499,
ACS Paragon Plus Environment
26

ACS Combinatorial Science
Page 28 of 39
1
2
1
3
4
1483, 1318, 1302, 1282, 1255, 1147; H NMR (500 MHz, CDCl3) δ: 2.25 (s, 3H), 2.64 (s, 3H),
5
6
7
8
6.72 (d, J = 7.8Hz, 2H), 6.93-6.97 (m, 2H), 7.00-7.09 (m, 3H), 7.19 (d, J = 7.6Hz, 2H), 7.47 (d, J
= 8.5Hz, 2H), 7.51 (s, 1H), 7.85 (d, J = 8.5Hz, 2H); 13C NMR (125MHz, CDCl3) δ: 11.79, 21.17,
112.62, 118.14, 123.89, 127.80, 127.93, 128.22, 128.49, 129.13, 129.44, 130.72, 131.16, 134.85,
137.61, 139.67, 140.41, 146.64, 186.95; HRMS calculated for C28H21ON5Cl (M+H): 478.14291
found 478.14386.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Compound 9{2,3}: Mp. 179-183 °C; 83mg (90%) of 9{2,3} was obtained as a light yellow solid
starting from 60mg of 8{2}: ESI MS (m/z): 462(M+H); IR (KBr, cm-1): 1662, 1625, 1593, 1558,
1
1499, 1463, 1446, 1319, 1301, 1271, 1252, 1227; H NMR (300 MHz, CDCl3) δ: 2.24 (s, 3H),
13
2.63 (s, 3H), 6.71 (d, J = 7.4Hz, 2H), 6.87-7.24 (m, 9H), 7.49 (s, 1H), 7.92-7.97 (m, 2H); C
NMR (75MHz, CDCl3) δ: 11.82, 21.21, 112.41, 115.93, 116.22, 118.17, 121.46, 123.90, 127.83,
128.03, 128.24, 128.53, 129.52, 130.74, 132.57, 132.72, 137.64, 139.67, 139.73, 146.65, 164.55,
167.95, 186.66; HRMS calculated for C28H21ON5F (M+H): 462.17247 found 462.17290.
Compound 9{2,4}: Mp. 167-168 °C; 81mg (85%) of 9{2,4} was obtained as a light yellow solid
starting from 60mg of 8{2}: ESI MS (m/z): 474(M+H); IR (KBr, cm-1): 1647, 1596, 1523, 1450,
1
1434, 1422, 1400, 1378, 1260, 1228; H NMR (500 MHz, CDCl3) δ: 2.24 (s, 3H), 2.62 (s, 3H),
3.88 (s, 3H), 6.71 (d, J = 7.5Hz, 2H), 6.88-6.99 (m, 4H), 7.02-7.09 (m, 3H), 7.19 (d, J = 7.6Hz,
2H), 7.42 (s, 1H), 7.92 (d, J = 8.7Hz, 2H); 13C NMR (125 MHz, CDCl3) δ: 11.75, 21.14, 55.56,
111.24, 114.04, 118.16, 121.43, 123.85, 127.64, 128.14, 128.20, 128.41, 128.44, 129.03, 129.99,
130.48, 132.45, 137.42, 139.47, 139.76, 146.33, 164.37, 186.60; HRMS calculated for
C29H24O2N5 (M+H): 474.19245 found 474.19347.
ACS Paragon Plus Environment
27

Page 29 of 39
ACS Combinatorial Science
1
2
3
4
5
6
Compound 9{2,5}: Mp. 199-201 °C; 95mg (91%) of 9{2,5} was obtained as a yellow solid
starting from 60mg of 8{2}: ESI MS (m/z): 520(M+H); IR (KBr, cm-1): 1645, 1598, 1557, 1524,
7
8
9
1
1463, 1447, 1317, 1306, 1275, 1259, 1225; H NMR (300 MHz, CDCl3) δ: 2.25 (s, 3H), 2.65 (s,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3H), 6.72 (d, J = 7.9Hz, 2H), 6.93-6.98 (m, 2H), 7.03-7.10 (m, 3H), 7.21 (d, J = 7.2Hz, 2H),
7.39-7.51 (m, 3H), 7.53 (s, 1H), 7.63-7.68 (m, 2H), 7.71 (d, J = 8.5Hz, 2H), 8.00 (d, J = 8.5Hz,
13
2H); C NMR (125 MHz, CDCl3) δ: 11.80, 21.17, 112.19, 118.19, 121.46, 123.89, 127.31,
127.41, 127.73, 128.11, 128.24, 128.38, 128.48, 128.96, 129.89, 130.53, 130.71, 135.07, 137.51,
139.59, 139.70, 139.77, 146.56, 146.56, 187.64; HRMS calculated for C34H26ON5 (M+H):
520.21319 found 520.21443.
General experimental procedure for the synthesis of fused 1,2,3-triazoloisoquinoline
11{1,2}-11{2,5}. To a stirred solution of 10{1}-10{2} (0.20 mmol) and 2-azido-1-(aryl)ethanone
2{2}-2{5} (0.20 mmol) in ethanol (2.0 mL) was added 0.20 mmol of piperidinium acetate and the
reaction mixture was heated under reflux for 12-24 h till complete consumption of the starting
substrates (TLC). Next ethanol was evaporated in vacuum and residue was extracted with
chloroform/water (15 mL each). The organic layer was separated, dried over anhydrous Na2SO4
and evaporated to yield crude which was purified through silica gel column chromatography
using ethyl acetate/hexane as eluent in increasing polarity.
Compound 11{1,2}: Mp. 184-186 °C; 65mg (85%) of 11{1,2} was obtained as a pale yellow
solid starting from 41mg of 10{1} : ESI MS (m/z): 384(M+H); IR (KBr, cm-1): 1671, 1625, 1588,
1
1553, 1487, 1458, 1446, 1280, 1242, 1204; H NMR (500 MHz, CDCl3) δ: 7.46-7.48 (m, 3H),
7.51-7.59 (m, 4H), 7.63 (dt, J = 7.5 & 0.7Hz, 1H), 7.76 (d, J = 6.9Hz, 2H), 7.85-7.89 (m, 3H),
8.24 (d, J = 8.1Hz, 1H); 13C NMR (125 MHz, CDCl3) δ: 119.18, 123.46, 124.48, 128.45, 128.50,
ACS Paragon Plus Environment
28